The Effect of Stress on Eating in Undergraduates-- Final
Susan stata.project-meta analysis
1. Nutrient Supplementation on the Health Status of Pre-Pubertal Children:
A Meta-Analysis
By: Susan Chen
ABSTRACT
Background:
Multiple studies have been carried out to assess the effect of nutrient supplements on
children’s health either through direct vitamin and mineral supplementation, food
fortification or both. The results of these studies are inconsistent, and the factors behind
these varied outcomes are unknown.
Objective:
Meta-analyses of randomized controlled trials, randomized placebo control trials and
retrospective difference-in-difference evaluations were therefore completed to assess the
effect of nutrient supplementation on the health of children ages 0-5 years in developing
countries.
Design:
A total of 18 acceptable studies published in the last 20 years were identified by searches
in journals of renowned reputation, such as The Lancet (American and British editions),
The Journal of Nutrition, The American Journal of Nutrition and The Journal of
Pediatrics. These studies identified clear outcomes that would measure changes in the
nutritional status of the population (mainly variations in stunting, wasting, infant
mortality, anemia). The factors associated with effect sizes were explored by meta-
regression techniques.
Results:
The overall effect of nutrition supplements on health outcomes was positive although the
studies indicate that nearly half of all interventions (7 out of 18 studies) had a neutral
effect. In this meta-analysis, the impacts might be influenced by design features such as
the type of intervention and sample size. The impacts might also vary by geographical
location and by infants who are breast-fed versus those who are not. However, a meta-
regression of these factors on study outcomes reveals that these factors are insignificant
(p>0.1).
Conclusions:
Interventions to improve children’s health should be considered in populations at risk of
undernourishment, especially where there are elevated rates of disease or mortality.
However, policymakers should think twice about distributing certain supplements, like
iron tablets, to children who have malaria or other diseases as preexisting underlying
conditions. In these cases, interventions to address malnutrition should be complemented
with interventions toward disease control and management.
2. INTRODUCTION
Micronutrients play a central part in metabolism and in the maintenance of tissue
function. For example, zinc plays a critical role in the cellular growth and metabolism in humans.
Zinc deficiency is associated with impaired growth, increased susceptibility to infections, and
other functional abnormalities (Institute of Medicine, 2001). Thus, an adequate nutrient intake is
necessary, but provision of excess supplements to people who do not need them may be harmful.
There is growing interest in the role of the micronutrients (vitamins and minerals) in
optimizing health, and in prevention or treatment of disease. This stems partly from the increase
in knowledge and understanding of the biochemical functions of these nutrients. The best
evidence for benefit is in children in developing countries consuming a deficient diet (seen in
some of the studies in this meta-analyses).
Since then, a considerable number of intervention trials have been completed in multiple
countries to assess the effect of nutrient supplements on children’s health. These studies have
yielded inconsistent results, however, possibly because of differences in 1) the preexisting health
status of the study subjects, 2) the content and availability of nutrients in the local diets, and 3)
the incidence of disease that can affect health independently of nutritional intervention.
Moreover, methodological aspects of these studies, such as variations in the nutrition dose and
method of administration may have influenced their results. Finally, in some cases, the sample
sizes may have been inadequate to detect potentially important differences in health with
statistical confidence.
For these reasons, a systematic, quantitative review of available studies is needed to
determine the overall effect of nutrient supplementation on children’s health. This review will
therefore consider current knowledge of the requirements in health, those people at risk of an
3. inadequate intake, and the conditions where supplements may be clinically required (Institute of
Medicine, 2001). The review will focus only on the generally accepted essential inorganic
micronutrients (trace elements) and organic micronutrients (fat soluble and water soluble
vitamins) for which deficiency states, with biochemical, physiological, or structural changes,
have been clearly reported—such states occur after prolonged consumption of a diet lacking the
single nutrient under consideration, and are uniquely remedied by including the nutrient back
into the diet.
I believe that a meta-analysis of several studies of mortality and morbidity will help to
make evidence-based recommendations for the role of nutrient supplementation in public health
policy to improve mortality, morbidity, growth, and development in young children. Therefore, I
completed a meta-analyses of intervention trials that were conducted to assess the effect of direct
vitamin and mineral supplementation, food fortification or both on pre-pubertal (ages 0-5 years)
children. I also explored characteristics of the study populations that could be used to predict
these responses to nutrient supplementation.
METHODS
Preliminary meta-analyses have been published previously on the effects of certain
nutrition supplements (iron, zinc, Vitamin A, etc) on specific health outcomes (height, weight,
mortality, etc). An example meta-analysis evaluated vitamin A supplementation on child
mortality (Fawzi, 1993). My meta-analyses differ from the earlier ones in several important
ways: 1) additional studies were identified by using a comprehensive bibliographic search in
several journals of renowned reputation and 2) a holistic approach was taken to evaluate general
health outcomes (improve or not improve health) through at least three different types of
interventions (address malnutrition either through direct vitamin and mineral supplementation,
4. food fortification or both). Furthermore, additional analyses were completed in the present
version to determine the characteristics of individual studies that may have influenced the
observed responses to supplemental nutrients.
Identification of studies
The studies considered for possible inclusion in the current meta-analyses were identified
by comprehensive searches in The Lancet (American and British editions), The Journal of
Nutrition, The American Journal of Nutrition and The Journal of Pediatrics. The studies of
choice were published within the last 20 years – 1991 to 2011. The studies were screened to
evaluate if they addressed undernourishment either through direct vitamin and mineral
supplementation, food fortification or both.
Inclusion criteria
Studies were considered for inclusion in the meta-analyses if they met the following criteria:
1) Provide a comparison between treatment and control groups - or before and after the
intervention, including randomized controlled trials, randomized placebo control trials
and retrospective difference-in-difference – evaluations.
2) Identify clear outcomes that would measure changes in the nutritional status of the
population.
3) Include sample sizes greater than 100.
4) Include at least five different covariates in the analyses, with special emphasis on age,
sex, and nutritional status at baseline, underlying diseases, ancillary interventions, and
maternal health.
5) Target the population of children and young infants between 0 and 60 months, or a
subgroup within (i.e. neonates between 0 - 90 days).
6) Target geographical areas known to have prevalent malnutrition (South East Asia, West
and East Africa and the Caribbean).
7) Provide adequate details about the design and implementation of the experiment, and the
statistical analysis completed to support conclusions.
5. I was intent on my identification of studies that met these criteria, and by doing so, found
studies of interest. Since no irrelevant studies were identified, no studies were excluded from my
meta-analyses. Irrelevant studies include those that target the elderly, include too few covariates,
intervene in developed countries, or have small sample sizes.
Review of studies and extraction of summary data
I assessed the suitability of 30 studies for inclusion in the meta-analyses, and the results
of these assessments were then independently re-evaluated. Consensus for inclusion relied on the
use of the pre-established inclusion criteria. Once the final set of studies for inclusion in the
analyses was established, I prepared written summaries of key descriptive information
concerning the study design, baseline characteristics of the study subjects, and outcomes of the
intervention. This summary is included in Table 1.
Analysis of data
The primary response variables included in each of the separate analyses were variations
in stunting, wasting, infant mortality, and anemia. For simplicity’s sake, I labeled the health
outcomes as positive (+1), negative (-1), or neutral (0). The use of effect sizes solves the problem
that the measurement units applied and the durations of observation were inconsistent by study.
Table 1: Summary of Studies
Author (Year) Location Outcomes Intervention / Program Impact Design Covariates Sample Size
Menon et al Haiti Change in Iron supplementation and food +1 RCT 8 425
(2005) health status fortification
Sedgh et al Sudan “ Vitamin A supplementation* +1 RCT 7 28,753
(2000)
Bryce et al Benin, “ Vitamin A and Iron/Folic Acid 0 Retrospective 14 6,820
(2010) Ghana, Mali supplementation during pregnancy Evaluation**
Andang’o et al Kenya “ High and low doses of Iron +1 RCT 14 505
(2007) supplementation
Sazawal et al Zanzibar “ Iron and Folic Acid +1 RCT 12 24,076
(2006) Supplementation***
6. Darboe et al Gambia “ Vitamin A supplementation 0 RCT 13 220
(2007)
Umeta et al Ethiopia “ Zinc supplementation +1 RCT 17 200
(2000)
Tielsch et al Nepal “ Iron and Zinc 0 RCT 13 41,276
(2007) supplementation***/****
Rahman et al Bangladesh “ Vitamin A and zinc +1 RCT 9 411
(2002) supplementation
Ruel et al Haiti “ Vitamin A supplementation +1 RCT 14 1,588
(2008)
SUMMIT Indonesia “ Multiple micronutrients +1 RCT 12 31,290
(2008) supplementation****
Vaidya et al Nepal “ Multiple micronutrient +1 RCT 19 917
(2008) supplementation*
Kerac et al Malawi “ Probiotics 0 RCT 30 795
(2009)
Verhoef et al Kenya “ High and low doses of Iron +1 RCT 24 516
(2002) supplementation
Kirkwood et al Ghana “ Vitamin A supplementation * 0 RCT 18 1455
(1996)
Ramakrishanan India “ Vitamin A supplementation 0 RCT 9 592
et al (1995)
West et al Nepal “ Vitamin A supplementation +1 RCT 7 24,085
(1991)
Sazawal et al. Zanzibar “ Zinc supplementation*** 0 RCT 12 42,546
(2007)
NB: Change in nutritional status includes increased weight and height (growth/stunting), decreased morbidity,
changes in mortality levels, vitamin levels, blood (anemia reduction, hemoglobin levels)
* Control group was not a placebo but another vitamin (E or iron and folic acid)
** Difference-in-difference analysis between treatment and country-level data based on Demographic and Health
Surveys and Multiple Indicator Cluster Surveys.
*** In addition, all groups received Vitamin A supplementation.
**** Control group was standard iron and folic acid supplementation.
The overall effect of nutrition supplements on health outcomes was positive (with a mean
impact of +0.611, shown in the blue line in Table 2), although the studies indicate that nearly
half of all interventions (7 out of 18 studies) had a middle-of-the-road effect.
To validate the findings, I have conducted a simple statistical analysis of factors that
might influence the estimated policy impact. In this meta-analysis, the impacts might be
influenced by design features such as the type of intervention and sample size. The impacts
might also vary by geographical location and infants that are breast-fed compared to those who
are not.
7. Table 2
Impact
Sazawal et al. (2007)
West et al (1991)
Ramakrishanan et al
Kirkwood et al (1996)
Verhoef et al (2002)
Kerac et al (2009)
Vaidya et al (2008)
SUMMIT (2008)
Ruel et al (2008)
Rahman et al (2002)
Impact
Tielsch et al (2007)
Umeta et al (2000)
Darboe et al (2007)
Sazawal et al (2006)
Andang’o et al (2007)
Bryce et al (2010)
Sedgh et al (2000)
Menon et al (2005)
0
0.5
1
Generally, none of these factors influenced my study. All the factors (type of
intervention, sample size, location, and breast-fed status) show insignificant p-values of p>0.1.
RESULTS
Description of studies and study subjects
Eighteen studies were considered acceptable for inclusion in the analyses. The general
characteristics of the studies and their participating subjects are shown in Table 1. The data sets
that were used for the present analyses provided information for 206,470 children in 14 different
countries where malnutrition is an issue. The 18 studies were published between 1991 and 2010
(median: 2006). The number of subjects per study ranged from 200 to 42,546 (mean: 11,470).
Ambiguous Results
8. In Sazawal et al (2009), there was a non-significant (p=0.29) reduction in the relative risk
of all cause mortality associated with zinc supplementation. In Kerac et al (2009), nutritional
findings were similar in both control and treatment groups (p=0.4). Thus, the probiotics did not
improve proscribed nutritional or clinical outcomes from severe acute malnutrition. In Tielsch et
al (2007), there were no significant differences in mortality between the zinc and placebo groups
(p<0.05). The frequency and duration of diarrhea, persistent diarrhea, dysentery, and acute lower
respiratory infections did not differ between the groups. In Darboe et al (2007), some trials have
shown possible adverse effects of higher doses of vitamin A (p<0.01). In Bryce et al (2010), the
researchers recorded no significant improvements in nutritional status attributable to vitamin A
supplements in the three countries. Mortality in children younger than 5 years decreased in
intervention areas by 13% in Benin (p=0.12), 20% in Ghana (p=0.10), and 24% in Mali
(p<0.0001), but these decreases were not greater than those in comparison areas in Benin (25%;
p=0.15) or Mali (31%; p=0.30). In Ramakrishanan et al (1995), the differences in growth
increments between the two groups were not statistically significant (the independent variables
are considered statistically significant for p<0.05). In Kirkwood et al (1996), vitamin A
supplementation did not lead to significant height increases in Ghanaian children (p>0.02).
Positive Results
In Umeta et al (2000), the length of stunted infants increased significantly more
(p<0.001) when supplemented with zinc than with placebo and the effect was greater (p<0.01)
than in non-stunted infants. Zinc supplementation also increased the weight of stunted children
(p<0.001) and of non-stunted children (p<0.05). In West et al (1991), the positive effect of
vitamin A supplementation was evident across age and gender (p<0.05). In Ruel et al (2008),
stunting, underweight, and wasting were 4–6 percentage points lower in preventive than in
9. recuperative communities; and mean anthropometric indicators were higher by +0.14 Z scores
(height for age; p=0.07), and +0.24 Z scores (weight for age and weight for height; p<0.0001). In
Vaidya et al (2008), the intervention group showed a slightly significant increase in weight-for-
age (p=0.048) after micronutrient supplementation. In the SUMMIT (2008) study, infants of
women consuming micronutrient supplements had an 18% reduction in early infant mortality
compared with those in the control group (p=0.01). Combined fetal loss and neonatal deaths
were reduced by 11% (p=0.045), with significant effects in infants of undernourished and anemic
women. In Sazawal et al (2006), those who received iron and folic acid with or without zinc
were 12% (p=0.02) more likely to die or need treatment in hospital for an adverse event and 11%
(p=0.03) more likely to be admitted to hospital; there were also 15% (p=0.19) more deaths in
these groups. In Verhoef et al (2002), the groups assigned iron plus sulfadoxine-pyrimethamine,
iron alone, or sulfadoxine-pyrimethamine alone had higher hemoglobin concentrations than the
group assigned placebo (p=0.08). In Andang’o et al (2007) the prevalence of iron-deficiency
anemia in children given flour fortified with high-dose iron edetic acid (NaFeEDTA), low-dose
NaFeEDTA, and electrolytic iron changed by −89%, −48%, and 59%, respectively. In Sedgh et
al (2000), children in the vitamin A intervention group grew 13 mm more during the study than
children in the control group (p=0.08). In Menon et al (2005), mean hemoglobin levels increased
for the children treated with micronutrient sprinkles (p<0.001). In Rahman et al (2002), joint zinc
and vitamin A supplementation improves vitamin A levels in vitamin A–deficient children
(p<0.05). Interestingly, zinc alone was associated with a significant increase in acute respiratory
infection, but this adverse effect was reduced by interaction between zinc and vitamin A.
Publication Bias
Formal analyses were completed to detect possible publication bias, which can occur
10. when authors fail to submit papers with insignificant results or journals fail to accept these
papers for publication. If publication bias is occurring, then studies with both small sample sizes
and small effect sizes are less likely to be found, resulting in a negative correlation between
absolute effect size and sample size. Therefore, one method of assessing publication bias is to
examine the correlation between effect size and sample size.
In each meta-analysis, the correlation between the number of subjects and the effect size
of individual studies was examined for possible publication bias. The correlation coefficients
ranged from –0.28 to 0.20, suggesting that there was not a problem with publication bias.
I also examined the strength of the conclusions by calculating how many additional
(possibly unpublished) studies with zero effect size would have to be available to negate the
slightly positive results of the current meta-analyses examining health improvements through
nutrient provision. Three more studies with ambiguous findings are necessary (bringing the total
negated effect studies to 10 (7+3) out of a possible 21 (18+3) studies.
DISCUSSION
Meta-analysis techniques are increasingly being used to consolidate results from multiple
studies of the same topic and to develop evidence-based policies for public health intervention.
The reliability of the conclusions derived from meta-analyses depends on the methodological
quality of the original studies, the appropriateness of the study inclusion criteria, and the
thoroughness of the review and synthesis of information.
In the current analyses, I included a sizeable number of rigorously designed intervention
trials of the effect of nutrient supplementation on children’s health outcomes. The results indicate
that changes in the nutritional status of the population (variations in stunting, wasting, infant
11. mortality, anemia) are positive in populations at risk of undernourishment, especially where there
are elevated rates of disease or mortality. However, certain supplements, like iron tablets, may
have adverse effects on children who have malaria or other diseases as preexisting underlying
conditions. In these cases, interventions to address malnutrition should be complemented with
interventions toward disease control and management.
The failure to identify any significant correlations between the sample sizes of individual
studies and the magnitude of the effect of supplementation suggests that these conclusions are
not likely to have been influenced by publication bias. The strength of the findings is further
supported by the fact that all of the studies included in the meta-analyses used a suitable clinical
trial design, including randomized controlled trials, randomized placebo control trials and
retrospective difference-in-difference evaluations, confirming that the supplements were
successfully delivered to the study subjects.
The criteria for inclusion of studies in the current analyses differed somewhat from
existing health provision meta-analyses studies. I was more holistic in my approach, looking at
the effect of three types of intervention- either through direct vitamin and mineral
supplementation, food fortification or both- on general health outcomes in children ages 0-5
years. Thus, it may not be appropriate to combine results from the different sets of study subjects
in a single meta-analysis. A more exacting meta-analyses looking at specific nutrient
supplements on certain health outcomes may be more suitable for generalizing findings and
translating results into policy interventions. Despite these changes in the inclusion criteria, the
results of the current analyses are generally consistent with previously published findings. The
positive effect of 0.611 is consistent with overall findings that nutrient supplementation can
produce positive health outcomes in undernourished children.
12. APPENDIX A
List of Studies and Authors
Study Author and Year
Micronutrient Sprinkles Reduce Anemia among 9- to 24-Mo-Old Children When Delivered
1 Menon et al (2005)
through an Integrated Health and Nutrition Program in Rural Haiti
Dietary Vitamin A Intake and Nondietary Factors Are Associated with Reversal of Stunting
2 Sedgh et al (2000)
in Children
The Accelerated Child Survival and Development programme in west Africa: a retrospective
3 Bryce et al (2010)
evaluation
Efficacy of iron-fortified whole maize flour on iron status of schoolchildren in Kenya: a Andang’o et al
4
randomised controlled trial (2007)
Effects of routine prophylactic supplementation with iron and folic acid on admission to
5 hospital and mortality in preschool children in a high malaria transmission setting: Sazawal et al (2006)
community-based, randomised, placebo-controlled trial
Effectiveness of an early supplementation scheme of high-dose vitamin A versus standard
6 Darboe et al (2007)
WHO protocol in Gambian mothers and infants: a randomised controlled trial
7 Zinc supplementation and stunted infants in Ethiopia: a randomised controlled trial Umeta et al (2000)
Effect of daily zinc supplementation on child mortality in southern Nepal: a community
8 Tielsch et al (2007)
based, cluster randomized, placebo-controlled trial
Effect of zinc supplementation on mortality in children aged 1–48 months: a community-
9 Sazawal et al. (2007)
based randomised placebo- controlled trial
Age-based preventive targeting of food assistance and behaviour change and communication
10 Ruel et al (2008)
for reduction of childhood undernutrition in Haiti: a cluster randomised trial
Synergistic effect of zinc and vitamin A on the biochemical indexes
11 Rahman et al (2002)
of vitamin A nutrition in children
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in
12 SUMMIT (2008)
Indonesia: a double-blind cluster-randomised trial
Effects of antenatal multiple micronutrient supplementation on children’s weight and size at
13 Vaidya et al (2008)
2 years of age in Nepal: follow-up of a double-blind randomised controlled trial
Probiotics and prebiotics for severe acute malnutrition (PRONUT study): a double-blind
14 Kerac et al (2009)
efficacy randomised controlled trial in Malawi
Intermittent administration of iron and sulfadoxine- pyrimethamine to control anaemia in
15 Verhoef et al (2002)
Kenyan children: a randomised controlled trial
Kirkwood et al
16 Effect of vitamin A supplementation on the growth of young children in northern Ghana
(1996)
Vitamin A Supplementation Does Not Improve Growth of Preschool Children: A Ramakrishanan et al
17
Randomized, Double-Blind Field Trial in South India (1995)
18 Efficacy of vitamin A in reducing preschool child mortality in Nepal West et al (1991)
13. APPENDIX B
STATA Outputs
NB: chg_stat_bin indicates the change in health status
1) Type of Intervention
. probit chg_stat_bin type_int
Probit regression Number of obs = 20
LR chi2(1) = 1.19
Prob > chi2 = 0.2756
Log likelihood = -12.865862 Pseudo R2 = 0.0442
chg_stat_bin Coef. Std. Err. z P>|z| [95% Conf.
Interval]
type_int -.7579695 .7164222 1.06 -0.290 -2.162131
.6461922
_cons .8416212 .6389635 1.32 0.188 -.4107241
2.093967
2) Breast-Fed Infants
. probit chg_stat_bin ante_bfeed
Probit regression Number of obs = 20
LR chi2(1) = 0.84
Prob > chi2 = 0.3593
Log likelihood = -13.040115 Pseudo R2 = 0.0312
chg_stat_bin Coef. Std. Err. z P>|z| [95% Conf.
Interval]
ante_bfeed .5244005 .5751444 0.91 0.362 -.6028617
1.651663
_cons 6.23e-17 .3963327 0.00 1.000 -.7767979
.7767979
3) Sample Size
. probit chg_stat_bin samp_size
Probit regression Number of obs = 20
LR chi2(1) = 0.16
Prob > chi2 = 0.6884
Log likelihood = -13.379798 Pseudo R2 = 0.0060
chg_stat_bin Coef. Std. Err. z P>|z| [95% Conf.
Interval]
samp_size -.2507149 .6274383 -0.40 0.689 -1.480471
.9790415
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